hcc experts round table...aos consensus1 (asian) 2009 chinese guidelines1 (china) 2011 jsh...

HCC EXPERTS ROUND TABLE(ASIA-PACIFIC)

Prof. Pierce Chow MBBS MMed, FAMS, FRCSE, PhD National Cancer Centre Singapore

and Singapore General Hospital

Singapore

OVERVIEW OF KEY DATAJuly 2020

2HCC, hepatocellular carcinoma

DISCLAIMER

Please note:

Views expressed within this presentation are the personal opinions of the author. They do not necessarily represent the views of the author’s academic institution, organisation, or other group or individual.

This content is supported by an Independent Educational Grant from Roche.

Disclosures:

Prof. Pierce Chow has received honoraria from the following: Sirtex Medical, Ipsen, Bristol-Myers Squibb, Oncosil, Bayer, New B Innovation, MSD, BTG Plc, Guerbet, Perspectum, IQVIA, Genentech, Roche, AstraZeneca, AUM Biosciences, L.E.K. Consulting Pte Ltd.

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EXECUTIVE SUMMARY

• The HCC Experts Round Table took place as two virtual meetings on 6 and 7 July 2020

• With 7 Experts from the Asia-Pacific region: – 1× Patient advocate– 1× Payer/health economics expert– 5× Physicians (representing hepatology, medical oncology, and surgery)

• 26 questions discussed:– 11 questions related to treatment of choice in advanced 1L HCC in Asia (sorafenib and lenvatinib)– 6 questions related to the management of advanced HCC patients in Asia (e.g. clinical setting, costs,

multidisciplinary tumour board)– 9 questions related to IMbrave150 data and potential impact in clinical practice in Asia

• Next step: Building a manuscript to reflect consensus outcomes

41L, first-line; HCC, hepatocellular carcinoma

INTRODUCTION AND

TREATMENT OVERVIEW OF

ADVANCED HCC


HEPATOCELLULAR CARCINOMA: ASIAN HCC GUIDELINES

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AOS; Asian Oncology Summit; APASL, Asian Pacific Association for the Study of the Liver; HCC, hepatocellular carcinoma; JSH, Japan Society of Hepatology; NCCSCG, National Cancer Centre Singapore Consensus Guidelines for HCC1. Tang H, et al. Transl Cancer Res. 2017;6:1214-225; 2. Lu S-N, et al. J Formos Med Assoc. 2018;117:381-403

Guidelines(country) Year

Content

Epidemiology Prevention Surveillance Staging & diagnosis Treatment Follow up

AOS consensus1

(Asian) 2009

Chinese guidelines1

(China) 2011

JSH guideline1

(Japan) 2014

Korean guidelines1 2015

Hong Kong consensus1 2015

NCCSCG1

(Singapore) 2016

APASL consensus guidelines1 (Asian) 2017

Taiwanese consensus2

(Taiwan) 2017

Guidelines(country) Year

ContentEpidemiology Prevention Surveillance Staging & diagnosis Treatment Follow up

AOS consensus1

(Asian) 2009 ✅ ✅ ✅ ✅ ✅ ❌

Chinese guidelines1

(China) 2011 ❌ ❌ ✅ ✅ ✅ ✅

JSH guideline1

(Japan) 2014 ❌ ❌ ✅ ✅ ✅ ❌

Korean guidelines1 2015 ✅ ✅ ✅ ✅ ✅ ✅

Hong Kong consensus1 2015 ❌ ❌ ❌ ✅ ✅ ❌

NCCSCG1

(Singapore) 2016 ❌ ❌ ❌ ✅ ✅ ❌

APASL consensus guidelines1 (Asian) 2017 ✅ ✅ ✅ ✅ ✅ ❌

Taiwanese consensus2

(Taiwan) 2017 ✅ ✅ ✅ ✅ ✅ ✅

HEPATOCELLULAR CARCINOMA: OVERVIEW

• The fourth most common cause of cancer-related death worldwide1

• HCC accounts for >80% of primary liver cancers worldwide1

• Chronic HBV and HCV infection are the most important causes of HCC and account for 80% of HCC cases globally1

• It is estimated that 72% of cases occur in Asia (more than 50% in China)2

• Staging of HCC is important to determine outcome and planning of optimal therapy. While there are a number staging systems used, the BCLC is currently commonly used to compare clinical outcomes:3

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BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; TACE, transarterial chemoembolisation 1. Yang JD, et al. Nat Rev Gastroenterol Hepatol. 2019;16:589-6042. Singal AG, et al. J Hepatol. 2020;72:250-613. Bruix J, et al. Nat Rev Gastroenterol Hepatol. 2019;16:617-30

BCLC staging Survival ratewith current therapy Standard of care treatment

Early and intermediate HCC

Stage 0-A >5 years Ablation, resection, transplantationStage B >2.5 years Chemoembolisation (TACE)

Advanced HCCStage C >1 year Systemic therapyStage D 3 months Best supportive care

SYSTEMIC TREATMENT SEQUENCING FOR BCLC STAGE C ADVANCED HCC• Targeted first-line therapies

– Combination: atezolizumab (PD-L1 inhibitor) + bevacizumab* (VEGF inhibitor) (US only)– Oral multikinase inhibitors: sorafenib and lenvatinib

• Targeted second-line therapies– Multikinase inhibitor: regorafenib– Multikinase inhibitor: cabozantinib– Anti-VEGFR (AFP ≥400 ng/mL) antibody: ramucirumab– PD-1 inhibitors: nivolumab, pembrolizumab (US only)– Immune therapy Combination: nivolumab + ipilimumab (US only)

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*The combination of atezolizumab + bevacizumab was approved by the US FDA on May 29. 2020AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PD-1, programmed death protein 1; PD-L1, programmed death-ligand 1; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptorSource: Bruix J, et al. Nat Rev Gastroenterol Hepatol. 2019;16:617-30

cabozantinib

cabozantinib

First line Second line Third lineregorafenib

ramucirumabnivolumab

pembrolizumabsorafenib

lenvatinib nivolumab + ipilimumab1

AFP ≥400 ng/mL

atezolizumab + bevacizumab1

SORAFENIB / LENVATINIBEFFICACY AND SAFETY DATA

IN 1L FOR ADVANCED HCC PATIENTS

91L, first-line; HCC, hepatocellular carcinoma

SORAFENIB EFFICACY DATABased on results from:

SHARP (NCT00105443): phase 3, international, multicentre, randomised, double blind, placebo-controlled study in 602 patients with hepatocellular carcinoma

Primary endpoint: OS Secondary endpoint: TTP

Population enrolled: BCLC stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%) in sorafenib and placebo respectively

Formulation: Film-coated tablets 200 mg

Recommended daily dose: 400 mg (2 × 200 mg tablets) twice daily

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BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; OS, overall survival; TTP, time to progressionSources: sorafenib summary of product characteristics dated November 2019; sorafenib US prescribing information dated June 2020

Efficacy parameter Sorafenib(n=299)

Placebo(n=303)

P-value HR (95% CI)

Median OS, months(95% CI)

10.7(9.4-13.3)

7.9(6.8-9.1) 0.00058 0.69

(0.55-0.87)

Median TTP, months(95% CI)

5.5(4.1-6.9)

2.8(2.7-3.9) 0.000007 0.58

(0.45-0.74)

LENVATINIB EFFICACY DATA

Based on results from:

REFLECT (NCT01761266): phase 3, international, multicentre, open-label, randomised study in 954 patients with hepatocellular carcinoma

à Non inferiority assessment of lenvatinib vs. sorafenib for OS

Primary endpoint: OS

Secondary endpoints: PFS, ORR (mRECIST and RECIST v1.1)

Population enrolled: BCLC stage B: 20%; stage C: 80%

Formulation: hard capsules 4 mg or 10 mg

Recommended dose daily: 12 mg (body weight ≥60 kg) or 8 mg (<60 kg)

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BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; mRECIST, modified RECIST; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours Sources: lenvatinib summary of product characteristics dated June 2020; lenvatinib US prescribing information dated February 2020

Efficacy parameters Lenvatinib SorafenibN=478 N=476

Overall survivalNumber of deaths (%) 351 (73) 350 (74)Median OS in months (95% CI) 13.6 (12.1-14.9) 12.3 (10.4-13.9)Hazard ratio (95% CI) 0.92 (0.79-1.06)Progression-free survival (mRECIST)Number of events (%) 311 (65) 323 (68)Median PFS in months (95% CI) 7.3 (5.6-7.5) 3.6 (3.6-3.7)Hazard ratio (95% CI) and P-value 0.64 (0.55-0.75); <0.001Objective response rate (mRECIST)Objective response rate 41% 12%

Complete responses, n (%) 10 (2.1) 4 (0.8)Partial responses, n (%) 184 (38.5) 55 (11.6)

95% CI (36-45) (10-16)P-value <0.001Progression-free survival (RECIST 1.1)Number of events (%) 307 (64) 320 (67)Median PFS in months (95% CI) 7.3 (5.6-7.5) 3.6 (3.6-3.9)Hazard ratio (95% CI) 0.65 (0.56-0.77)Objective response rate (RECIST 1.1)Objective response rate 19% 7%

Complete responses, n (%) 2 (0.4) 1 (0.2)Partial responses, n (%) 88 (18.4) 30 (6.3)

95% CI (15-22) (4-9)

SORAFENIB AND LENVATINIB SAFETY DATA IN HCC PATIENTS

Further and more detailed information about safety profile of both products and their management can be found in the European SmPC and USPI

12HCC, hepatocellular carcinoma; SmPC, summary of product characteristics; USPI, US prescribing informationSources: sorafenib SmPC November 2019; sorafenib USPI June 2020; lenvatinib SmPC June 2020; lenvatinib USPI February 2020

Most common adverse reactions (≥20%)

sorafenib-treated patients in SHARP trial

Diarrhoea – fatigue – hand-foot skin reaction – weight loss – anorexia –nausea – abdominal pain

lenvatinib-treated patients in REFLECT trial

Hypertension – fatigue – diarrhoea – decreased appetite –arthralgia/myalgia – decreased weight – abdominal pain – palmar-plantar erythrodysesthesia syndrome – proteinuria – dysphonia – haemorrhagic events – hypothyroidism – nausea

IMbrave150:A STUDY OF ATEZOLIZUMAB IN COMBINATION

WITH BEVACIZUMAB COMPARED WITH SORAFENIB IN PATIENTS WITH UNTREATED LOCALLY ADVANCED

OR METASTATIC HCC

ClinicalTrials.gov Identifier: NCT03434379


IMbrave150 CLINICAL TRIALDESIGN

IMbrave150 (NCT03434379): randomized phase 3 trial assessing combination therapy with the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab versus standard-of-care sorafenib in first line for advanced HCC

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AFP, alpha-fetoprotein; BID, twice a day; ECOG PS; Eastern Cooperative Oncology Group performance status; HCC; hepatocellular carcinoma; IRF, independent review facility; IV, intravenous; mRECIST, modified RECIST; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PRO, patient-reported outcome; q3w, every 3 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumours;VEGF, vascular endothelial growth factorFinn RS, et al. N Engl J Med. 2020;382:1894-905

(Open label)

Co-primary endpoints• OS• IRF-assessed PFS per RECIST 1.1

Secondary endpoints include• IRF-assessed ORR per RECIST 1.1 and HCC mRECIST• PROs

Key eligibility criteria• Locally advanced metastatic

or unresectable HCC• ECOG PS 0-1• No prior systemic therapy• No bleeding or high risk

of bleeding(n=501)

Stratification criteria

• Region: Asia (excluding Japan) or rest of world

• ECOG PS 0 or 1

• Presence or absence of macrovascular invasion or extrahepatic spread

• Baseline AFP <400 or ≥400 ng/mL

Survival follow-up

Until loss of clinical benefit

or unacceptable

toxicity

R 2:1

sorafenib400 mg BID

atezolizumab1200 mg IV q3w + bevacizumab

15 mg/kg IV q3w

IMbrave150 CLINICAL TRIALEFFICACY RESULTS: PRIMARY ENDPOINTS

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CI, confidence interval; HR, hazard ratio; IRF, independent review facility; NE, not evaluable; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid TumoursFinn RS, et al. N Engl J Med. 2020;382:1894-905

atezolizumab + bevacizumab (n=336)

sorafenib(n=165)

Median OS (95% CI), months NE 13.2 (10.4–NE)

OS, HR (95% CI) 0.58(0.42–0.79)

P-value <0.001

Median PFS (95% CI) per IRF RECIST v1.1, months

6.8(5.7–8.3)

4.3(4.0–5.6)

PFS, HR (95% CI) 0.59(0.47–0.76)

P-value <0.001

IMbrave150 CLINICAL TRIALEFFICACY RESULTS: SECONDARY ENDPOINTS

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CI, confidence interval; HCC, hepatocellular carcinoma; IRF, independent review facility; mRECIST, modified RECIST; ORR, objective response rate; RECIST, Response Evaluation Criteria in Solid TumoursFinn RS, et al. N Engl J Med. 2020;382:1894-905


sorafenib(n=159)

Confirmed ORR per IRF RECIST v1.1, % (95% CI)

27.3(22.5–32.5)

11.9(7.4–18.0)

P-value <0.001


sorafenib(n=158)

Confirmed ORR per HCC specific mRECIST, % (95% CI)

33.2(28.1–38.6)

13.3(8.4–19.6)

P-value <0.001

IMbrave150 CLINICAL TRIALSAFETY RESULTS

17AEs, adverse eventsFinn RS, et al. N Engl J Med. 2020;382:1894-905

Variables, n (%) atezolizumab + bevacizumab(n=329)

sorafenib(n=156)

Patients with an AE from any cause 323 (98.2) 154 (98.7)

Grade 3-4 AEs (numbers represents the highest grades assigned) 186 (56.5) 86 (55.1)

Grade 5 AEs 15* (4.6) 9** (5.8)

Serious adverse event 125 (38.0) 48 (30.8)

AEs leading to withdrawal from any trial drug 51 (15.5) 16 (10.3)

AEs leading to dose modification or interruption of any trial drug 163 (49.5) 95 (60.9)

Dose interruption of any trial treatment 163 (49.5) 64 (41.0)

Dose modification of sorafenib – 58 (37.2)

*Grade 5 events in the atezolizumab–bevacizumab group: gastrointestinal haemorrhage (in 3 patients), pneumonia (in 2 patients), empyema, gastric ulcer perforation, abnormal hepatic function, liver injury, multiple-organ dysfunction syndrome, oesophageal varices haemorrhage, subarachnoid haemorrhage, respiratory distress, sepsis, and cardiac arrest (in 1 patient each)

**Grade 5 events in the sorafenib group:death (in 2 patients), hepatic cirrhosis (in 2 patients), cardiac arrest, cardiac failure, general physical health deterioration, hepatitis E, and peritoneal haemorrhage (in 1 patient each)

IMbrave150 CLINICAL TRIALCONCLUSION

• IMbrave150 demonstrated a statistically significant improvement in OS and PFS with atezolizumab + bevacizumab versus sorafenib in the first-line setting in patients with advanced HCC

• atezolizumab + bevacizumab: approved by US FDA on 29 May 2020 as first-line systemic therapy for advanced HCC

• Times to response were similar in the combination and sorafenib arms

• Response rates were significantly higher in the combination arm

• The trial was conducted in a patient population that had preserved liver function (Child–Pugh class A) and a decreased risk of variceal bleeding. The safety of the combination in a broader population warrants further study

18FDA, Food and Drug Administration; HCC; hepatocellular carcinoma; OS, overall survival; PFS; progression-free survivalFinn RS, et al. N Engl J Med. 2020;382:1894-905

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hcc experts round table...aos consensus1 (asian) 2009 chinese guidelines1 (china) 2011 jsh...

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